Downregulation of a GPCR by β-Arrestin2-Mediated Switch from an Endosomal to a TGN Recycling Pathway.
Downregulation of a GPCR by β-Arrestin2-Mediated Switch from an Endosomal to a TGN Recycling Pathway.
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DOI：
10.1016/j.celrep.2016.11.050
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发表时间：
2016-12-13
期刊：
影响因子：
8.8
通讯作者：
McGraw TE
中科院分区：
文献类型：
--
作者：
Abdullah N;Beg M;Soares D;Dittman JS;McGraw TE
葡萄糖依赖型促胰岛素多肽(GIP)是一种参与营养动态平衡的胰岛素激素。GIP受体(GIPR)被结构性内化并返回到质膜，这是G蛋白偶联受体(GPCR)的非典型行为。GIP通过抑制循环而不影响内化来促进GIPR从质膜下调。这种短暂的脱敏是通过改变激活的GIPR在细胞内的运输来实现的。GIP刺激诱导GIPR循环从快速的内体途径切换到缓慢的TGN途径。GPCRK和β-arrestin2是这种循环转换所必需的。GIPR的一个编码序列变体与代谢变化有关，它改变了激活后的运输，其特征是下调增强和脱敏时间延长。该变异体的下调需要β-arrestin2靶向TGN，但不依赖于GPCRK酶。变异体中的单一氨基酸替代偏向于促进GIP刺激β-arrestin2的募集，而不是受体的磷酸化，从而加强下调。
Glucose-dependent insulinotropic polypeptide (GIP) is an incretin hormone involved in nutrient homeostasis. GIP receptor (GIPR) is constitutively internalized and returned to the plasma membrane, atypical behavior for a G protein-coupled receptor (GPCR). GIP promotes GIPR downregulation from the plasma membrane by inhibiting recycling without affecting internalization. This transient desensitization is achieved by altered intracellular trafficking of activated GIPR. GIP stimulation induces a switch in GIPR recycling from a rapid endosomal to a slow TGN pathway. GPCR kinases and β-arrestin2 are required for this switch in recycling. A coding sequence variant of GIPR, which has been associated with metabolic alterations, has altered post-activation trafficking characterized by enhanced downregulation and prolonged desensitization. Downregulation of the variant requires β-arrestin2 targeting to the TGN but is independent of GPCR kinases. The single amino acid substitution in the variant biases the receptor to promote GIP stimulated β-arrestin2 recruitment without receptor phosphorylation, thereby enhancing downregulation.
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影响因子：
64.8
作者：
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